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Development of Novel Polymeric Micellar DACHPt for Enhanced Platinum Based Chemotherapy in Colorectal Cancer

  • Author / Creator
    Abdulsalam Alharbi
  • One of the major limitations of chemotherapy in cancer treatment is the side effects of anti-cancer drugs. This happens due to non-selective distribution of most standard chemotherapies, and their action on cancer and all normal dividing cells. The objective of this project is to develop a novel delivery system for the more potent parent compound of oxaliplatin, dichloro (1,2-diaminocyclohexane) platinum(II) (DACHPt) to limit its non-selective distribution to normal tissues, thus reducing the drug's side effects. As an alternative to prodrug strategy, incorporation of DACHPt in polymeric micellar nanocarriers was hypothesized to increase DACHPt aqueous solubility and increase platinium delivery to colorectal cancerous tissues, while reducing platinum concentrations in normal tissues. Methoxy poly (ethylene oxide)-block-poly-(α-carboxylate-ε-caprolactone) (PEO-b-PCCL) diblock copolymers were used to prepare micelles containing DACHPt through polymer-metal complex formation of DACHPt with PEO-b-PCCL (abbreviated as DACHPt-PCCL) in distilled water. The mean diameter of the prepared micelles was measured using dynamic light scattering (DLS) to be 60 nm. The release profile of DACHPt from DACHPt-PCCL micelles as measured by ICP-MS showed only 53.6% of platinum was released after 120 h from micelles compared to 96.5% platinum release from free drug at 7.5 h confirming drug complexation. The critical micelle concentration (CMC) and kinetic stability of DACHPt-PCCL micelles in the presence of sodium dodecyl sulfate (SDS), studied using dynamic DLS. The results showed CMC at micromolar level and high kinetic stability for micelles in the presence of SDS implying micellar stability following dilution. DACHPt-PCCL micelles were able to increase the solubility of DACHPt from 0.25 mg/mL to 4.1 mg/mL (16 times) due to the high drug loading inside PEO-b-PCCL micelles (20 % w/w). The relative IC50 of DACHPt-PCCL micelles against human colorectal cancer cell lines, HCT116, HT29 and SW620, as measured by MTT assay was higher than DACHPt; perhaps due to the slow release of platinum complexes from DACHPt-PCCL micelles and/or slower cell uptake. Free DACHPt showed higher cell uptake in HT29 cell line, and similar cell uptake in HCT116 and SW620 cell lines compared to DACHPt-PCCL micelles. The in vivo tissue distribution study in NIH-III mice bearing subcutaneous HCT116 tumors, 24 h following tail vein injection of DACHPt-PCCL micelles at a dose of 6 mg platinum/kg, showed higher platinum concentrations in plasma compared to animals injected with oxaliplatin, at the same platinum dose that led to a trending, but statistically non-significant increase in tumor platinum levels. Overall, our results point to a potential for DACHPt-PCCL micelles in delivery of DACHPt to colorectal cancer tissues.

  • Subjects / Keywords
  • Graduation date
    Spring 2019
  • Type of Item
    Thesis
  • Degree
    Master of Science
  • DOI
    https://doi.org/10.7939/r3-j2d6-r603
  • License
    Permission is hereby granted to the University of Alberta Libraries to reproduce single copies of this thesis and to lend or sell such copies for private, scholarly or scientific research purposes only. Where the thesis is converted to, or otherwise made available in digital form, the University of Alberta will advise potential users of the thesis of these terms. The author reserves all other publication and other rights in association with the copyright in the thesis and, except as herein before provided, neither the thesis nor any substantial portion thereof may be printed or otherwise reproduced in any material form whatsoever without the author's prior written permission.